Tucatinib/HP Maintenance Boosts PFS in Metastatic HER2+ Breast Cancer

For patients with HER2-positive metastatic breast cancer who had not experienced disease progression while on docetaxel plus trastuzumab and pertuzumab (THP), using tucatinib (Tukysa) combined with trastuzumab (Herceptin) and pertuzumab (Perjeta; HP) as frontline maintenance therapy resulted in a significant improvement in investigator-assessed progression-free survival (PFS) compared to using placebo plus HP.¹

Topline results from the phase 3 HER2CLIMB-05 trial (NCT05132582) were first announced in October 2025, indicating that the study had met its primary end point.² A preliminary look at the data, which were presented at the 2025 San Antonio Breast Cancer Symposium with median follow-up of approximately 23 months, demonstrated that the median PFS was 24.9 months (95% CI, 21.3–not available [NA]) with tucatinib/HP (n = 326) vs 16.3 months (95% CI, 12.6–18.7) with placebo/HP (n = 328; HR, 0.641; 95% CI, 0.514–0.799; P <.0001).¹

The PFS benefit with tucatinib also extended across all prespecified patient subgroups, which looked at diagnosis (de novo or recurrent), hormone receptor status (negative or positive), brain metastases at baseline (yes or no), prior anti–HER2 therapy (yes or no), best response to THP induction (complete response [CR]/partial response [PR] or stable disease/non-CR/PR), disease type (visceral or nonvisceral), ECOG performance status (0 or 1), region (North America or Europe or Asia Pacific or rest of the world), age (<65 or ≥65), and race (White or Asian or other).

“HER2CLIMB-05 has demonstrated that the addition of tucatinib to HP represents an enhanced frontline maintenance therapy option for patients with HER2-positive metastatic breast cancer, providing an opportunity to prolong time to disease progression and time off chemotherapy,” Erika Hamilton, MD, lead study author and director of breast cancer research at Sarah Cannon Research Institute in Nashville, Tennessee, said during a press briefing.

HER2CLIMB-05 Background

First-line treatment for patients with HER2-positive metastatic breast cancer typically includes taxane-based chemotherapy with HP, followed by HP maintenance, but disease progression often prevents patients from reaching second-line therapy. Prior data from the pivotal phase 2 HER2CLIMB trial (NCT02614794) showed that adding tucatinib to capecitabine and trastuzumab improved PFS and overall survival (OS) even in heavily pretreated populations, including those with brain metastases. HER2CLIMB-05 was launched to evaluate whether incorporating tucatinib into first-line maintenance with HP could further enhance outcomes by intensifying both extracellular and intracellular HER2 targeting.

HER2CLIMB-05 is a randomized, double-blind, placebo-controlled, international, phase 3 trial that enrolled patients with centrally confirmed HER2-positive metastatic breast cancer with no evidence of progression after 4 to 8 cycles of THP, no or asymptomatic brain metastases confirmed by contrast-enhanced MRI at screening, and an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to 300 mg of oral tucatinib twice daily (n = 326) or matched placebo (n = 328), both in combination with HP once every 21 days with or without endocrine therapy. Trastuzumab was administered intravenously (IV) at 6 mg/kg or 600 mg subcutaneously (SC) and pertuzumab was given at 420 mg IV. The fixed-dose SC combination of 600 mg of trastuzumab, 600 mg of pertuzumab, and 20,000 units of hyaluronidase-zzxf (Phesgo) was also allowed.

Therapy was continued until unacceptable toxicity, disease progression, consent withdrawal, or study closure. Crossover was prohibited.

The primary end point was investigator-assessed PFS per RECIST 1.1 criteria. Secondary end points were OS, PFS per blinded independent central review, central nervous system PFS, safety, health-related quality of life, and pharmacokinetics.

Patients were stratified by diagnosis (de novo or recurrent), hormone receptor status (positive or negative), and presence or history of brain metastases (yes or no).

Efficacy Data

With respect to PFS benefit according to hormone receptor status, greater benefit was seen in the hormone receptor–negative population although still present in the hormone receptor–positive population.

In the former cohort, the median PFS was 24.9 months (95% CI, 19.4–NA) with tucatinib (n = 158) vs 12.6 months (95% CI, 9.4–16.8) with placebo (n = 152; HR, 0.554; 95% CI, 0.403–0.761; P =.0002). In the latter cohort, the median PFS in the tucatinib (n = 168) and placebo (n = 176) arms was 25.0 months (95% CI, 16.5–NA) and 18.1 months (95% CI, 13.0–20.8), respectively (HR, 0.725; 95% CI, 0.535–0.983; P =.0389).

Assessment of the key secondary end point of the trial pointed to a numerical trend for OS improvement in the tucatinib arm (HR, 0.539; 95% CI, 0.303–0.957; P =.0320).

Safety Profile

“The tucatinib and HP combination showed a manageable safety profile, with diarrhea, nausea, and elevated liver enzymes, mostly of low grade, being the most common adverse effects [AEs],” Hamilton reported.

Safety was evaluated in all patients who were randomly assigned and received at least 1 dose of study therapy. Notably, if a patient discontinued trastuzumab or pertuzumab they were required to discontinue both agents.

The median duration of tucatinib (n = 326) and placebo (n = 324) therapy was 17.1 months (range, 0.4-36.5) and 15.5 months (95% CI, 0.5–41.3), respectively. Treatment-emergent AEs (TEAEs) occurred in 99.1% and 96.6% of patients in the tucatinib and placebo arms, respectively. In the tucatinib arm, the rates of grade 3 or greater TEAEs, serious TEAEs, and TEAEs leading to death were 43.2%, 16.9%, and 0.3%, respectively. These respective rates in the placebo arm were 24.4%, 8.0%, and 0.3%.

TEAEs leading to treatment discontinuation occurred in 13.8% and 4.6% of patients in the tucatinib and placebo arms, respectively. The rates of discontinuation for tucatinib/placebo, individually administered HP, or fixed-dose HP were 13.5%, 0.6%, and 2.8%, respectively, in the tucatinib arm and 2.2%, 1.5%, and 1.2% in the placebo arm.

The most common TEAEs leading to tucatinib or placebo discontinuation were hepatic events (tucatinib, 7.7%; placebo, 0%) and diarrhea (1.5%; 0.9%). Dose modification because of a TEAE was reported in 55.8% and 34.6% of patients in the tucatinib and placebo arms, respectively. TEAEs leading to tucatinib dose hold or reduction occurred in 49.4% and 29.1% of patients, respectively; these respective rates for placebo were 25.3% and 11.1% in the placebo arm.

DISCLOSURES: Hamilton disclosed being a consultant/Advisor for: Pfizer Inc, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis GmbH, Verascity Science, Theratechnologies, Accutar Biotech, Entos, Fosun Pharma, Gilead Sciences, Jaxx Pharmaceuticals, MphaR, Zentalis, Jefferies, and Tempus; receiving research funding from: AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millennium, TapImmune Inc., Lilly, Pfizer Inc, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Harpoon, Black Diamond Therapeutics, Orinove, Molecular Templates, Seagen, Compugen, G1 Therapeutics, Karyopharm Therapeutics, Dana Farber Cancer Hospital, Onconova Therapeutics, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akeso Biopharma, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repertoire Immune Medicines, Treadwell Therapeutics, Jacobio, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, ProfoundBio, Cullinan Oncology, Bristol-Myers Squibb, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, and Stemline Therapeutics.

REFERENCES

1. Hamilton E, Curigliano G, Martin M, et al. HER2CLIMB-05: A randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS1-01.

2. Tukysa combination significantly improves progression-free survival as first-line maintenance in HER2+ metastatic breast cancer in HER2CLIMB-05 trial. News release. Pfizer. October 14, 2025. Accessed December 10, 2025. https://tinyurl.com/yjytdvw4